We propose the planning of a pre-NPEBC Center for Multiscale Analysis of Complex Physiological Systems, with the overall goal of understanding specific systems, and mathematical, computational and biological issues involved in scale-up. The knowledge explosion in biomedicine, matched by revolutionary advances in computational technology and mathematical algorithms enable the attack on problems of a complexity that was heretofore beyond reach. A new and genuinely multidisciplinary approach, anchored in research on specific biomedical problems, will be required to realize the potential of these developments. The Center will be planned to develop such an approach. The Development Projects focus on neuronal functions at the molecular and cellular levels ( Modeling interactions and networks in the cell), as well as at the multicellular and tissue level ( Modeling the function of neural circuits), and on analysis at the integrated organ level ( Modeling physiology and pathophysiology in the cardiovascular system). The biological and computational issues involve scale-up to progressively more complex levels in order to understand physiological processes and diseases. One example is development of adaptation and tolerance in higher order neuronal functions underlying the addictive state, with insights expected about 1)- how such tolerance can be attributed to specific cellular components and molecular processes in complex cell and multi-cell systems responsible for integrated functions, and 2)- how pharmacological challenges, e.g., from medication or drugs of abuse, modulate integrated functions. Multi-scale analysis should reveal how external stimuli can reset systems behavior so that repeated external stimulus (e.g. drug use) is needed to maintain homeostasis of systems behaviors, including in the addicted state. New methods for quantitative analysis and modeling of the heart will be developed to understand pathophysiology (sudden cardiac death and malignant ventricular arrhythmias) in terms of molecular components and processes. Insights from simulations of stimuli in the heart from medication and drug abuse could parallel those done for neuronal systems, enabling cross-reference and validation between neuronal and cardiac systems. New computational tools, including for imaging will be fostered in the Center's Tools Core that will serve as well in dissemination and curation. Educational programs for faculty and students (including MS and PhD degrees) will be developed in an Education Core to sustain and disseminate the multidisciplinary science of the Center.